Obesity is a major problem worldwide that increases risk for a wide range of diseases, including diabetes and heart disease. Extensive research in recent years has unraveled many cellular mechanisms in obesity, integrating metabolic signals and inflammatory pathways. Endoplasmic reticulum (ER) stress has been shown to play an important role in metabolic diseases and is linked to both metabolic and immune regulation. While the cellular mechanisms linking overnutrition to ER stress, inflammation and disruption of insulin signal transduction have been extensively studied, the adaptation at the tissue level as a network of living and communicating cells has not been explored. In recent years, it has been shown that gap junction channels play a pivotal role in tissue adaptation to stress and inflammation in various tissues and pathophysiological conditions. Gap junctions facilitate direct cytoplasmic communication between neighboring cells, allowing the transfer of small-molecular-weight molecules involved in cell signaling and metabolism and promoting tissue survival. Assessing the potential role of cell-cell communication through gap junctions in obesity and diabetes in metabolically relevant tissues such as liver and adipose tissue is the primary focus of this proposal. The overarching hypothesis of this project is that obesity-induced ER stress in liver and adipose tissue requires increased gap junction mediated cell-cell communication in order to manage stress and to maintain tissue function and whole-body metabolic homeostasis. Abnormal activation of liver and/or adipose tissue gap junctions may, therefore, represent a novel mechanism for obesity induced metabolic abnormalities. The aim of this study is to assess the potential role of the gap junction proteins (connexins [Cxs]) in the adaptation of liver and adipose tissue to ER stress, overnutrition and obesity. The regulation of connexins under these conditions will be studied, as will their potential to improve tissue dysfunction and whole-body metabolism in obesity and diabetes. A thorough understanding of the plausible role of gap junction communication in maintaining metabolic homeostasis in normal physiology and under conditions of nutrient excess is important to fully understand, and to subsequently treat, chronic metabolic diseases.